Method of treating jaundice in animals

ABSTRACT

A METHOD OF TREATING AN ANIMAL SUFFERING FROM JAUNDICE WHICH COMPRISES ADMINSTERING TO THE ANIMAL A PHARMACOLOGICALLY EFFECTIVE JAUNDICE TREATMETN AMOUNT OF A COMPOUND 1-PHENYL-5,5-DIETHYL BARABITURIC ACID.

United States Patent METHOD OF TREATING :IAUNDICE IN ANIMALS Allan H.Conney, Westchester, and John J. Burns, New York, N.Y., assignors toBurroughs Wellcome Co., Tuckahoe, NY.

No Drawing. Original application June 15, 1966, Ser. No. 557,606.Divided and this application Nov. 6, 1969, Ser. No. 871,259

Int. Cl. A61k 27/00 US. Cl. 424-254 4 Claims ABSTRACT OF THE DISCLOSUREA method of treating an animal suffering from jaundice which comprisesadministering to the animal a pharmacologically efiective jaundicetreatment amount of a compound 1-phenyl-5,5-diethyl barbituric acid.

This application is a division of U.S. application Ser. No. 557,606,filed June 15, 1966, now abandoned.

This invention relates to methods of treating and prophylaxes forvarious ailments and more particularly relates to methods forstimulating enzymatic oxidations.

It is well known that a major process, by Which drugs and othersubstances are eliminated from or modified in the body is throughoxidation. While a number of oxidative processes exist, the specificconcern of the instant invention is hydroxylation carried out by enzymeslocated particularly in the microsomes of body cells and notably inliver cells. The oxidations with which these enzymes are especiallyconcerned are hydroxylations, that is, replacement of a hydrogen boundto carbon by a hydroxyl group. Thus, for example, a phenyl group may behydroxylated, usually para to the main atachment, to becomephydroxyphenyl.

Still another type of hydroxylation takes place with steroid compoundswhich may be hydroxylated in various places, the 6-position especially.This often results in conversion to steroids which are relatively inertphysiologically. It is believed that enhanced oxidative ability producedby the treatment of this invention is due to the activation of theprocess in the body for forming oxidative enzymes. This has beenverified in tests made on newborn animals, where oxidative ability isvirtually absent before treatment. In such cases new oxidative enzymesmust have been made as a result of the treatment.

The teachings of this invention may be applied to the treatment ofnewborn infants or other individuals, that are afflicted with jaundicedue to a low excretion rate of bilirubin. This excretion of bilirubin ispreceded by conjugation to a glucuronide involving oxidative processes.

Applicants have discovered that Phetharbital, formerly known by othernames such as 1-phenyl-5,5-diethyl barbituric acid, l-phenyl barbital,or pyrictal, which has previously been used in the treatment of febrileconvulsions of children (see US. Pat. 2,955,073) may be used to produceincreased enzymatic activity which will lead to the hydroxylation ofsteroids. Applicants have discovered that the above-mentioned ailmentmay be treated by the administration of such drug. Phetharbital isphysiologically rather inert as a drug and, accordingly, has a lowdegree of toxicity. It is itself oxidized fairly rapidly and isexecreted preponderantly as N-p-hydroxyphenyl barbital. Doses of up to600 mg. intravenously have been given to ice? human volunteers with noside effects observable beyond mild sedation. Oral doses of 1 gram werewell tolerated. Rats have been given as much as 5 grams/kg./day, indiet, during chronic toxicity studies, without serious injury. Animalsreceiving 2.5 grams/kg./ day were normal in all observations.

Patients, such as man or animal, treated for the abovementioned ailmentor to produce increased enzymatic activity, would be given dosagesranging from about 1 mg./ kg. (body Weight)/day, to about 40mg./kg.(body weight) /day, the preferable dosage being between 5-20 mg./kg. /day. The drug may be administered intravenously or, preferably,orally. Extensive studies have shown that phetharbital is a strongenzyme inducer and stimulates a variety of oxidations.

In Table I there is shown the effect of pretreatment with phetharbitalon the microsomal oxidation of cortisol in guinea pigs. Themicrosome-suspensions were made by the method described by Conney etal., in Journal of Pharmacology and Experimental Therapeutics, (30, 1,1960).

Table H included herein demonstrates increased metabolism ofhexobarbital and zoxazolamine. Table III shows increased metabolism ofdiphenyl hydantoin, Table IV illustrates the effect of theadministration of pyrictal on phenylbutazone.

Accordingly, the substance of the present invention relies on the methodof treating and stimulating enzymatic oxidative processes in vivo for atherapeutic purpose, one of which has been exemplified above.

TABLE I Increased Activity of Cortisol (SB-Hydroxylase in LiverMicrosomes of Guinea Pigs Treated With Phetharbital and Other Drugs for4 days in experiment 3. Liver microsomes from 660 mg. of liver wereincubated for 30 minutes at 37 with 100 m moles of cortisol-4-C in thepresence of a system that generates reduced triphosphopyridinenucleotide.

TABLE II Effect of Phetharbital and Phenobarbital On the Duration ofAction of Hexobarbital and Zoxazolamine Duration of Duration ofhexobarbital zoxazolamine sleep paralysis Pretreatment (minutes)(minutes) Control 167=|=l4 336:1:55 Phetharbital 2714 865:7Phenobarbital 43:1 79 10 Male rats weighing 45 g. were injected i.p.twice daily with 37 mg./kg. of barbiturate for 4 days. On the fifth daythey received a single i.p. injection of 100 mg./kg. of hexobarbital ormg./kg. of zoxazolamine. Each value represents the average and standarderror obtained from 10 rats.

Stimulatory effect of phetharbital on diphenylhydantoin TABLE IVmetabohsm dogs Efieet of Phetharbital and Phenobarbital OnPhenylbutazone Plasma Diphenylhydantoin was administered intravenouslyto Level dogs in a dose of 50 mg./ kg. and plasma levels of the drugPlasma phenylwere determined at various times over the following 6 5Daily m1 g fi g hours. The dogs were given phenobarbital or phetharbitaldosage Of 25 me/ -norally for 16 to 70 days, and plasma levels ofdiphenylhy- Pretreatment (mg/kg) dogs dantoin were again determinedafter an intravenous dose Nonem. 6 64. 0:114. 7 of the drug. The resultsin Table III show that chronic ifigggg gfitg 11:11:: 2% i 3; treatmentwith the barbiturates stimulated markedly the 1D f 1 4 t1 metabolism ofdiphenylhydantoin- The half'life of Pl i e r ii l fi t z dii iv givdiip. a1 sa1.25% solution of the sodium salt phenylhydantoin in controldogs averaged 7.3 hours, whereas the half-life of diphenylhydantoin indogs pretreated with phetharbital or phenobarbital was 2.3 and 2.1 Whatis claimed is: hours, respectively. In accord with these results, theplas- 15 1. The method of treating an animal suffering from ma levels ofdiphenylhydantoin in drug-treated dogs at 6 jaundice which comprisesadministering a pharmacologhours after diphenylhydantoin were aboutOne-fifth of ically effective jaundice treatment amount of the comthosefound before pretreatment with the enzyme stimu. pound1-phenyl-5,5-diethyl barbituric acid to the sufferlators. The dogstreated chronically with phetharbital ing animal. failed to show thesedation observed in the phenobarbital 2. The method according to claim1 in which the comtreated animals. pound is administered intravenously.

TABLE III Stimulatory Effect of phetharbital and phenobarbital ondiphenylhydantoin (DPH) metabolism in dogs Before treatment Aftertreatment Daily Duration Half-life dosage 1 of dOsage of DPH 2 Dog No.Sex Drug treatment (mg./kg.) (days) (hours) M Phenobarbital 16 70 5. 5

F do 16 7.1

1 Drugs were given orally in divided doses twice daily. 1Diphenylhydantoin (50 mgJkg.) was given intravenously to all dogs exceptnumber 4, which received the drug intraperitoneally.

Stimulatory effect of phetharbital on phenylbutazone 3. The methodaccording to claim 1 in which the commetabolism in dogs pound isadministered orally.

4. The method according to claim 1 in which 1 mg./kg.

Phenylbutazone is metabolized slowly in the dog, and a 45 to 40 m an-malb d ht d t plasma level of about 64 mg./liter is obtained at 7 hours g gl o y Welg 1S a mum ered dafly' after a 25 mg./ kg. i.p. dose. However,the drug was metab- References Cited olized much more rapidly when dogswere pretreated with UNITED STATES PATENTS phetharbital orphenobarbital. Under these conditions, the 2 955 073 10/1960 de Beerplasma level of phenylbutazone at 7 hours averaged only 5 15 and 19mg./l., respectively (Table IV). JEROME D. GOLDBERG, Primary Examiner

